|Publication number||US8033083 B2|
|Application number||US 12/687,976|
|Publication date||Oct 11, 2011|
|Filing date||Jan 15, 2010|
|Priority date||Jul 30, 2004|
|Also published as||CA2574912A1, EP1786378A2, US7669388, US20080216452, US20100115751, WO2006010635A2, WO2006010635A3, WO2006010635A8|
|Publication number||12687976, 687976, US 8033083 B2, US 8033083B2, US-B2-8033083, US8033083 B2, US8033083B2|
|Original Assignee||Merrion Research Iii Limited|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (30), Non-Patent Citations (4), Classifications (20), Legal Events (1)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application is a continuation of U.S. application Ser. No. 11/572,838 filed on Jan. 29, 2007, now U.S. Pat. No. 7,669,388 which is a 35 U.S.C. §371 national phase application of PCT Application No. EP2005/00831 filed on Aug. 1, 2005 which claims the priority of U.S. Provisional Application No. 60/592,454 filed Jul. 30, 2004, the disclosure of which are hereby incorporated herein by reference in their entireties.
The present invention relates to a process and an apparatus for the automated manufacture of a gastro-retentive device. An example of such a device is a retard form of the type disclosed in U.S. Pat. No. 4,996,058, which is hereby incorporated herein by reference, although the present invention is not limited to such retard forms and is applicable to any gastro-retentive device.
The term “retard form,” denotes a dosage form which effects delayed release of at least a portion of the active ingredient in the stomach and to the upper part of the small intestine in comparison to conventional dosage forms, such as customary tablets or capsules. Avoiding an undesirably high initial dose, the release is effected continuously over a relatively long period and controlled at an effective level. The retard form is administered orally and, once in contact with the stomach fluids, expands so as to float on the stomach fluids and/or be retained within the space of the stomach due to its size following inflation, which precludes passage across the pylorus sphincter. In this manner it remains in the stomach to insure continuous controlled release of the physiologically active ingredients.
A retard form is characterized preferably, at least in one form, by the following: (a) at least one component that expands on contact with bodily fluid (e.g., a substance that generates or constitutes a blowing agent), and/or a physiologically active substance, and/or a combination of physiologically active substances, and/or optionally a pharmaceutically acceptable hydrophilic swelling agent and further pharmaceutically acceptable adjuncts, (b) at least one hydrophilic membrane which surrounds component (a) and which is expansible at the site of use and is permeable to body fluid, and (c) a covering which surrounds component (a) and membrane (b) and which disintegrates without delay under the action of bodily fluid at the site of use in the stomach, e.g., a gelatin capsule.
As an example, a retard form of this type suitable for the present invention could take the following form. A component (a) is provided in the form of a tablet surrounded by and sealed within component (b) in the form of a hydrophilic membrane or film, the membrane forming a pouch in which the tablet sits. The tablet and membrane assembly are fitted within component (c) provided in the form of a gelatin capsule.
Taken orally, the retard form moves to the stomach where the gelatin capsule disintegrates to release the tablet membrane assembly. Upon contact with stomach fluid, the tablet generates the blowing agent, for example carbon dioxide gas. The gas causes the membrane surrounding the tablet to inflate, forming a gas-filled “bag.” This gas-filled “bag” is able to float on the stomach fluids and/or is unable to pass through the pylorus sphincter following inflation, and thus is retained in the stomach. During its dwell time in the stomach, any active ingredients present in the tablet are released slowly and/or in a controlled manner into the surrounding body fluid, preferably by diffusion, through the membrane. Since gastric juice is being transported further into the upper part of the small intestine, the active ingredient passes continuously and over a prolonged period into the duodenum and jejunum, where it can be absorbed over an extended period. The retard form ensures continuous release of any active ingredient in conjunction with uniform absorption, or at least that the device will remain in the stomach for the desired time period. Once the gas generating components are used up, and/or the when the “bag” deflates to a certain size, the remainder of the device can pass through the body.
The manufacture of a gastro-retentive device of the general type described above can be complex and includes several challenges. The component(s) (a) or tablet must be sealed within the membrane(s) to form the pouch. Depending on the drug or drugs of choice, the tablet may also contain other excipients which control the release of the drug or drugs from the tablet into the medium of the pouch and subsequently into the gastric fluid of the stomach following diffusion across the pouch. Once formed, the pouch must be folded to fit within the capsule. While such gastro-retentive devices can be produced manually, it is believed that an automated and economical process for producing such forms will help bring the benefits of gastro-retentive devices to the public.
The present invention provides a method and apparatus for the automated manufacture of a dosage form that requires folding or wrapping for insertion into a capsule. One such dosage form, by example, is a gastro-retentive device that preferably has at least the following components: 1) an ingredient section which includes a physiologically active substance or substances and optionally a gas generating substance, 2) a film or membrane surrounding the ingredient section so as to form a pouch that has at least one flap, the combination of the ingredients and the pouch being referred to as a pouch assembly, and 3) a capsule surrounding the pouch assembly and which is capable of disintegrating upon contact with bodily fluids to release the pouch assembly, the capsule having first and second cap sections. The method includes the steps of providing a continuous strip of pouch assemblies, separating a single pouch assembly from the strip; wrapping the flap of the pouch assembly, inserting the folded pouch assembly into the first cap section; and inserting the first cap/pouch assembly into the second cap section to complete an encapsulation of the pouch assembly. Other dosage forms are believed possible to which the present invention will apply. An apparatus for carrying out the above method is also provided.
The following detailed description will be better understood when read in conjunction with the figures appended hereto. For the purpose of illustrating the invention, there is shown in the drawings a preferred embodiment. It is understood, however, that this invention is not limited to this embodiment or the precise arrangements shown.
The present invention provides a novel method for making a gastro-retentive device. The method of the present invention permits automation of the manufacturing process and allows the economical and reliable manufacture of such forms.
An apparatus for carrying out the method of the present invention is also provided.
An exemplary gastro-retentive device 10 to be manufactured in accordance with the present invention is illustrated with reference to
With particular reference to
Surrounding the folded ingredient section 12 is a film or membrane 14 (an example being component (b) as described in the background section), configured to form a pouch 16 which is inflatable upon the generation of gas from the ingredient section 12 within to form a gas-filled “bag.” The membrane is preferably provided in two layers, a bottom layer 14 a and top layer 14 b, with the ingredient section 12 sandwiched in between. The two membrane layers 14 a, 14 b are heat sealed together to form the sealed pouch 16. The areas of the pouch surrounding the ingredient section 12 are referred to as flaps 15 a, 15 b. (There may also be front and back flaps 17 a, 17 b). The flaps include any evacuated portion of the pouch 16 extending from the ingredient section 12. The membrane film preferred is a polyvinylaclcohol (PVA) having a thickness of approximately 150 μm (±10 μm), and which is typically formed of two membrane layers sealed together. The pouch 16 is preferably between about 20 mm×20 mm and 25 mm×25 mm inside dimensions although other sizes may be suitable depending on the desired use. The seal width is preferably about 2 mm to 3 mm in addition to the inside dimensions indicated all around the pouch. The combination of the ingredient section 12 and pouch 16 will be referred to herein as the ingredient/pouch assembly 18, or pouch assembly 18, as shown in
Surrounding the ingredient/pouch assembly 18 is a capsule 20 (component c as discussed in the background section) having a first capsule section 20 a (the capsule body), and a second capsule section 20 b (the capsule cap). See
One method of making the retard form 10 of the present invention begins with the manufacture of the pouch assembly 18. Shown in
A tablet 13 is controllably released from the hopper 26 onto the lower membrane layer 14 a in the desired orientation. The upper membrane layer 14 b is then laid on top of the tablet 13. (With films that have a backing, the backing is rewound for removal and disposal). The machine 24 automatically punches a hole in at least one of the films 14 a, 14 b through which air can be evacuated during a subsequent sealing process. Alternatives are possible. With the tablet sandwiched between the two films 14 a, 14 b, the films are pressed together and the air between the two layers evacuated through the punched hole to a desired vacuum level.
The two films are then sealed together with a heating element pressed into contact with the film to produce a seal around the tablet 13, preferably air tight, of about 2 to 3 mm in width (the air evacuation hole being on the outside of the seal), thereby forming the sealed tablet/pouch assembly 18. The sealing temperature is preferably between 200-210° C. with a dwell time of about two seconds. The machine 24 can produce multiple tablet/pouch assemblies 18 during each cycle, the completed tablet/pouch assemblies forming a continuous strip 32 of tablet/pouch assemblies 18 which can be rolled up into a spool 34, or fed directly to a tablet pouch fold encapsulation machine for further processing as described below. The machine 24 can be controlled by a programmable controller as is known in the art. Other evacuation and sealing methods are contemplated. For example, three of the four sides of the films/tablet assembly could be heat sealed first, then the air evacuated from the pressed films/tablet assembly on the unsealed side, followed by sealing the last side. Moreover, the tablet can be inserted into the pouch after the three sides are sealed, the fourth side then being sealed after the tablet is inserted and the air evacuated by vacuum.
Other means of making the tablet/pouch assembly 18 are known. For example, a customized machine from Prodo-Pak Corporation of Garfield, N.J., USA, model number RV 925 WS-4 pouch forming and sealing machine, can be used.
A preferred embodiment of a pouch wrap and encapsulation machine 100 is now described with reference to
With reference to
The empty gelatin capsules 20, each having a first capsule section (capsule body) 20 a and second capsule section (capsule cap) 20 b, are fed to the machine 100 by a capsule feeder 110 supported above the machine 100 (shown partially in
The first wheel 102, referred to herein as the capsule load and separation wheel, is preferably approximately 12 inches in diameter with 48 evenly spaced cylindrical openings 114 near the wheel perimeter. With further reference to
For further processing, the capsule sections 20 a and 20 b are separated within the openings 114. A pair of hollow vacuum rods 124, each having a concave end matching the shape of the end of the capsule bodies 20 a, and having a vacuum port 124 a for gripping the capsule body, are moved into the opening 114 to grip the capsule bodies 20 a and move them leftwardly to the opposite end of the openings 114 as oriented in
With reference to
The third wheel 106, referred to herein as the pouch wrap and insert wheel, receives the capsule bodies 20 a from the first wheel 102 (the capsule load and separation wheel). The wheel 106 shown is preferably 12 inches in diameter with 48 evenly spaced openings 136 near the wheel perimeter. As illustrated in
As noted above, the second wheel 104, in addition to receiving the capsule caps 20 b from the wheel 102, also receives the capsule bodies 20 a from the wheel 106 after the pouch assemblies 18 have been inserted therein (forming the capsule body/pouch assemblies 144), to combine the two capsule sections 20 a, 20 b and complete the encapsulation process. See
After receiving the body/pouch assemblies 144 at the pouch pressing section 164, the third wheel 106 indexes in the direction of arrow 140 (
To effectuate the transfer and encapsulation process, a pair of cam operated push rods 156 having ends to match the curvature of the capsule bodies 20 a advance to push the capsule body/pouch assemblies 144 from the wheel 106 through the openings 154 and into the openings 128 of wheel 104, and then dwell to prevent back sliding of the capsule body/pouch assemblies 144. A pair of cam operated capsule cap push rods 158 advance into the opening 128 of the wheel 104 to push the capsule caps 20 b onto the capsule bodies 20 a of the capsule body/pouch assemblies 144 a sufficient distance to lock the capsule sections 20 a, 20 b together as is known in the art, forming the encapsulated dosage forms 10. The push rods 156 thereafter push the dosage form 10 fully into the openings 128 of wheel 104. Both push rods 156, 158 then retract from respective openings 136, 128, to leave the dosage form 10 in the opening 128 of wheel 104.
With further reference to
Having described the various steps carried out by use of the wheels 102, 106, and 104, the steps of providing and wrapping the pouch assemblies 18 at pouch processing section 164 are now described in further detail. With reference to
The pouch load subassembly 166 has a pouch strip servo-index system 170 (
The outer vacuum heads 172 are stationary and have vacuum ports configured preferably to hold the top portion of the strips 32 thereto. They also have channels 176 in which the ingredient section 12 of the pouch assembly can fit for slidable movement without damage (see also
For an index movement to the right as shown in
The delivered pouch assemblies 18, while held by vacuum to the pouch load tooling mechanism 168 (held by the vacuum heads 184 as seen in
After the pouch assemblies 18 are cut from the strips 32, the vacuum in the inner vacuum head 174 is turned off to release the strips 32, and the vacuum in the outer vacuum heads 172 is turned on to grip the strips 32 (
The pouch load tooling member 168 receives the individual pouch assemblies 18, grips them for the cutting process described above, and then transports them downward to the pouch wrapping subassembly 148 where the pouch assemblies 18 are wrapped. With reference to
When the motion vacuum heads 184 are in the lower position as illustrated in
With continued reference to
In the pouch wrapping subassembly 148, the pouch flaps 15 a, 15 b are folded/wrapped after which the wrapped pouches are inserted into capsule bodies 20 a by the pouch insert subassembly 200. As the pouch wrapping subassembly 148 and pouch insert subassembly 200 use similar elements, description of the two subassemblies is now described in further detail.
With reference to
With further reference to
With further reference to
Thus, with reference to
Once the flaps are wrapped, a pouch insert subassembly 200 inserts the wrapped pouch into a capsule body 20 a. With reference to
With the pouch assemblies 18 inserted into the capsule bodies 20 a, the wheel 106 indexes forward in the direction of arrow 140 (
Having described the arrangements of the various elements of the machine 100, the sequence of steps carried out by the machine 100 is now described with reference to
The capsule feed tubes 112 are filled with capsules 20 oriented such that the capsule bodies 20 a enter the wheel 102 openings 114 first at wheel index position 116. After the capsules 20 are inserted into the openings 114 and separated therein into capsule bodies 20 a and capsule caps 20 b, the wheel 102 is indexed in the direction of arrow 126 (
With each index movement of the wheels, the pouch assemblies 18 are fed into the machine 100 via the pouch load subassembly 166 which uses the pouch servo-index system 170 to move the pouch assemblies. The pouch assemblies 18 are cut from the strips 32 by cutters 180 and transferred downward by the pouch load tooling mechanism 168 to the wrapping cavities 202 of the pouch wrapping subassembly 148.
Once the pouch assemblies 18 are positioned in the wrapping cavities 202, the wrapping forks 212 advance into the wrapping cavities 202 and rotate to wrap the pouch assemblies 18. Push rods 244 then advance to push the wrapped pouches through the funnel plate 246 into capsule bodies 20 a held in openings 136 of the third wheel 106 by push rods 252 to prevent movement of the capsule body during the insertion process.
When the capsule body/pouches 144 in wheel 106 move to the wheel index position 150, the capsule body/pouches 144 are transferred from wheel 106 to openings 128 in wheel 104 through the spacer plate 152 to the wheel 106 and combined with capsule caps 20 b to complete the encapsulation process. The wheel 106 then indexes to index position 160 where the completed gastro-retentive devices 10 are pushed out of the openings (
It is seen that the various steps described above take place simultaneously after each indexing of the wheels, the process being repeated in a continuous manner for each set of pouch assemblies 18 and capsules 20. For example, after an index movement of the wheels 102, 104, 106, a new set of capsules 20 are loaded into the wheel 102 and separated into capsule bodies 20 a and caps 20 b, a set of capsule caps 20 b is transferred from wheel 102 to wheel 104 at index position 130, a set of cap bodies 20 a is transferred from wheel 102 to wheel 106 at index position 138, pouch assemblies are transferred to the stationary vacuum head 182 and cut from strip 30, pouch assemblies 18 are loaded into cap bodies 20 a in wheel 106 at insert subassembly 200, capsule bodies 20 a containing pouch assemblies 18 are combined with capsule caps 20 b and transferred from wheel 106 to wheel 104 at index position 150, and encapsulated pouches (gastro-retentive device 10) are off loaded at index position 160. The wheels then index and the process begins again.
Various control systems can be used to control the operation of the machine 100 as is known in the art. For example, with reference to
Any suitable materials as known in the art may be sued for the various components. For example, ANSI 316 Stainless Steel may be used for product contact surfaces. These surfaces and associated welds should be polished to a number 7 mirror finish. ANSI 304 Stainless Steel may be used elsewhere. A number 4 finish can be provided for naked (non-shed) metallic non-product contact surfaces and welds.
The present invention as described above provides an economical means of producing an advantageous gastro-retentive form 10. It is understood that the above described embodiment is a preferred embodiment of the invention, and that it is not intended to limit the invention to such disclosure. Changes and modifications may be incorporated and embodied within the scope of the invention.
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|1||Notification Concerning Transmittal of International Preliminary Report on Patentability (Chapter I of the Patent Cooperation Treaty) corresponding to European Patent Application No. EP2005/008310 mailed Feb. 23, 2007.|
|2||Notification Concerning Transmittal of International Preliminary Report on Patentability (Chapter I of the Patent Cooperation Treaty) corresponding to International Application No. PCT/IB2004/003414 mailed Feb. 16, 2006.|
|3||Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration corresponding to European Patent Application No. EP2005/008310 mailed Mar. 6, 2006.|
|4||Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration corresponding to International Application No. PCT/IB2004/003414 mailed May 31, 2005.|
|U.S. Classification||53/468, 53/381.1, 53/454, 53/266.1, 53/492|
|Cooperative Classification||A61K9/4808, A61K9/009, A61K9/0065, A61J3/074, B65B25/145, A61J3/071, Y10T29/49819, Y10T29/53539, B65B5/04, B65B63/024|
|European Classification||B65B25/14C, A61J3/07B, A61J3/07B2, B65B63/02C|